Beyond dopamine: dual neuromodulator regulation of motor variability and learning

项目摘要 学习和表演复杂的技能，如演讲或音乐，需要精确控制运动的变异性。 虽然运动变异性的提高可以刺激新行为的学习，但过度的变异性可能会损害 表现学到的技能。大脑如何在学习过程中和专家中控制运动变异性 业绩仍不明朗。有趣的是，基底节(BG)是运动可变性的重要来源。 健康和疾病，是多巴胺(DA)加强更多成功行为的关键部位。的确， 大脑皮层调节运动变异性的能力对语音等复杂的顺序技能尤为关键， 其中，可变性既可以出现在初级运动“音节”的水平上，也可以出现在其中的顺序“句法”水平上 这些音节是有条理的。大脑皮层DA信号如何影响学习过程中的运动变异性 人们很难理解类似于演讲或音乐的复杂的连续技能。此外，与其单独行动，还不如 新的观点认为，DA信号受到其他信号分子的强烈调制，如腺苷 (ADO)，它可以跟踪与广泛运动练习相关的代谢成本。在这里，我将描述 BG中ADO和DA的释放是如何相互关联的，与运动可变性以及学习 发声运动序列。在直接服务于大脑计划目标时，我将结合尖端计算 以及光学工具，以及一种创新的分子遗传学方法来剖析神经调节剂和细胞- 类型对运动变异性和学习的具体贡献。我的具体目标是：1)将ADO和DA形象 青少年声乐学习中的SBG。2)确定SBG ADO规范变异性和检验的必要性 用于ADO和DA版本之间的直接联系。3)从基因上标记“间接的”和“直接的”棘神经元类型 并评估Ado如何调节他们的活动来影响歌曲的可变性。单独来说，每个目标都会移动 超越BG技能学习的单一神经调节器模型，它们将共同帮助揭示基本的 在学习和表现过程中控制运动变异性的机制。我将在以下条件下进行这项研究 理查德·穆尼博士、乔希·黄博士和约翰·皮尔森博士的监督 成就卓著的导师，为我提供行为、系统神经科学方面的补充专业知识， 计算和尖端的遗传技术。除了我对了解自然环境的浓厚兴趣 对于行为学习的形式，我带来了自己在分析行为方面的专业知识，并与光学方法相结合。 这项建议将使我能够加深和拓宽我的专业知识，并将在以下方面提供重要的培训 新的行为、计算、遗传和成像技术。这种对系统的综合方法 神经科学和自然行为将增强我作为独立研究人员的能力 解决大脑倡议的目标。

Project Summary Learning and performing complex skills such as speech or music requires precise control of motor variability. While elevated motor variability can spur the learning of new behaviors, excessive variability can impair performance of learned skills. How the brain controls motor variability during learning and in expert performance remains unclear. Intriguingly, the basal ganglia (BG) is an important source of motor variability in both health and disease, and is a key site where dopamine (DA) reinforces more successful behaviors. Indeed, the BG’s ability to regulate motor variability is especially critical for complex sequential skills such as speech, where variability can arise at both the level of elementary motor “syllables” and the sequential “syntax” in which these syllables are organized. How DA signaling in the BG influences motor variability during the learning of complex sequential skills akin to speech or music is poorly understood. Moreover, rather than acting alone, an emerging view is that DA signaling is strongly modulated by other signaling molecules, such as adenosine (Ado), which may track the metabolic costs associated with extensive motor practice. Here I will characterize how Ado and DA release in the BG are related to each other, to motor variability, and to the learning of vocal motor sequences. In direct service of BRAIN initiative goals, I will combine cutting-edge computational and optical tools along with an innovative molecular-genetic approach to dissect both neuromodulator and cell- type specific contributions to motor variability and learning. My Specific Aims are: 1) To image Ado and DA in the sBG during juvenile vocal learning. 2) To establish the necessity of sBG Ado to regulate variability and test for a direct link between Ado and DA release. 3) To genetically tag “indirect” and “direct” spiny neuron types and assess how Ado modulates their activity to influence song variability. Individually, each aim will move beyond a single-neuromodulator model of BG skill learning, and collectively they will help reveal fundamental mechanisms that control motor variability across learning and performance. I will conduct this research under the supervision of Drs. Richard Mooney, Josh Huang, and John Pearson, an interdisciplinary team of accomplished mentors that provides me with complementary expertise in behavioral, systems neuroscience, computational, and cutting-edge genetic techniques. In addition to my deep interest in understanding natural forms of behavioral learning, I bring my own expertise in analyzing behavior in concert with optical methods. This proposal will allow me to both deepen and broaden my expertise, and will provide significant training in novel behavioral, computational, genetic, and imaging techniques. This integrative approach to systems neuroscience and natural behavior will enhance my capabilities as an independent researcher while addressing BRAIN Initiative goals.